PROJECT SUMMARY Polychlorinated biphenyls (PCBs) continue to persist in our environment and are linked to multiple threats to human health. Of most recent concern is the ongoing contamination by volatile PCBs in both outdoor and indoor air as a result of their presence in older buildings (e.g., public schools), at sites near legacy pollution with PCBs, and due to current inadvertent industrial production of these agents. PCBs with lower numbers of chlorine atoms are more volatile and are also more readily metabolized. Such metabolism may result in either detoxication or creation of more toxic metabolites. Project 3 is focused on the interactions of hydroxylated metabolites derived from PCBs with mammalian cytosolic sulfotransferases (SULTs). Hydroxylated PCBs (OH- PCBs) may serve as either substrates for sulfation catalyzed by SULTs or inhibitors of the physiological sulfation reactions that these enzymes catalyze. The long term goal of Project 3 is to understand the relationships between human SULTs and toxic responses to the lower chlorinated PCBs present in air. A central hypothesis for the upcoming project period is that SULTs catalyze the sulfation of hydroxylated metabolites of the major lower chlorinated PCBs found in air samples, and that the resulting PCB sulfates have biological effects that include transport to relevant tissues via serum proteins and alterations in thyroid hormone concentrations and/or steroid hormone sulfation. We have determined that lower chlorinated PCB sulfates are high affinity ligands for the thyroxine-binding site on transthyretin. Previous studies also indicate that OH-PCBs can either inhibit or serve as substrates for hSULT2A1 and hSULT1E1, enzymes that function to inactivate steroid hormones via sulfation. During the upcoming project period we will: 1) identify the specificities of key enzymes catalyzing the sulfation of physiological steroids with respect to their interactions with OH-PCB and PCB sulfate metabolites of the most frequently detected PCBs in air samples, 2) determine the binding affinities of PCB sulfates with serum thyroid hormone transport proteins, evaluate the potential for alteration of thyroid hormone concentrations, and determine the distribution of PCB sulfates to relevant tissues, and 3) evaluate the enzymatic potential for metabolic generation of PCB sulfates in humans and relate this to concentrations of sulfated PCB metabolites in human serum and urine samples. We believe that the proposed studies are highly innovative due to the fact that the sulfated metabolites of PCBs have been an overlooked class of metabolites of these environmental contaminants. Moreover, high affinity of some of these PCB sulfates for thyroxine-binding sites on serum proteins may facilitate transport to tissues with subsequent toxicological effects. The proposed research in this project is highly interactive with multiple projects and cores of the Iowa Superfund Research Program, and the results to be forthcoming will yield new insights that will be important in achieving the center-wide goals relating to evaluation and prioritization of risks associated with airborne PCBs.